Building quality into a coating process.

An effective approach towards optimal development strategy is to use the quality by design principle. However, this approach can first be implemented when possible risks impacting critical quality attributes are defined and interactions between those are fully understood. The objective of this study was to identify critical variables that affect the final modified release product performance using a risk management approach with supporting statistical tool. After risk ranking and filtering a full mixed factorial experimental design of coating experiments was performed. Experimental design clearly indicated that studied critical processes parameters have a great impact on coat integrity and hence on drug release.

Helium pycnometry as a tool for assessment of sealing efficiency in microencapsulation.

There is a need for a fast and reliable method to evaluate the development in coating quality during coating, especially for fast dissolving coatings. In the present study, pycnometric density was evaluated as a tool for assessment of coating quality in terms of sealing efficiency for microspheres coated with polymeric aqueous solutions. Further, it was investigated if the method could be used to study effects of spray variables on the sealing efficiency of coated microspheres. The microcrystalline cellulose particles Ethispheres250 were coated with aqueous solutions of Hypromellose 5 and Povidone K-90F by Wurster bottom-spray technique. End products and samples drawn during coating were analysed in terms of pycnometric helium density and scanning electron microscopy (SEM). Experiments constituted a 2(3) factorial design with the following spray related variables: atomisation air flow, polymer type, and solution concentration/viscosity. Helium pycnometric density was seen to lower gradually during coating in all experiments and to follow a common pattern. The quantitative lowering in density was further seen to correlate to sealing of voids by gradual covering of the microsphere surface and thus the sealing efficiency. Hence, the present data suggests helium pycnometry as a tool for assessment of coating quality in terms of sealing efficiency. This goes particularly for testing of products coated with water-soluble coatings, where dissolution testing obviously is compromised. The specific data on sealing efficiency might also add to other analytical methods in the analysis of coating quality, in general. End point densities of coated microspheres were seen to reveal differences in sealing efficiency between polymers. Measured densities of final products were also generally seen to reflect differences in coating permeability caused by variations in spray conditions. Thus, the measurement of density is a potential a tool for evaluation of spray conditions with respect to sealing of microspheres and identification of critical spray conditions.

Factors influencing the in vitro deposition of tobramycin aerosol: a comparison of an ultrasonic nebulizer and a high-frequency vibrating mesh nebulizer.

The aim of the study was to elaborate recommendations for inhalation during mechanical ventilation that could optimize delivery. Delivery of aerosols in vitro from nebulizers during mechanical ventilation is dependent on the dimensions of the ventilator circuit, the nebulizer type, and the ventilator settings. A review of the literature shows that some ventilator settings have a larger influence on the amount of aerosol delivered than others. It has been shown in an in vitro model that the factors influencing delivered aerosol are the ventilator flow rate, the diameter of the endotracheal tube, and the time spent in inspiration (all p < 0.05). Two different nebulizer types were used in the study: an ultrasonic nebulizer (SUN 345) and a high-frequency vibrating mesh nebulizer (Aeroneb Pro). No difference in the amount delivered was seen with different nebulizer types (p = 0.215). For optimizing the amount delivered, the largest possible flow, endotracheal tube, and time spent in inspiration should be used.

Investigation and comparison of performance of effervescent and standard pneumatic atomizer intended for soluble aqueous coating.

Effervescent atomizers belong to the group of internal mixing atomizers. The effervescent approach might be a potential alternative to traditional atomization techniques, e.g., for applications where low atomization air consumption is advantageous In this paper, performance of one proposed design of the effervescent atomizer is investigated and compared to that of a standard pneumatic atomizer. The purpose of the comparison is to evaluate the actual potential of the specific effervescent atomizer in pharmaceutical relevant aqueous coating applications. Aqueous solutions of Hypromellose 5 as well as Povidone K-90F were characterized in terms of rheological properties and surface tension. Solutions were atomized by means of a standard Schlick pneumatic atomizer as well as a customized inside-out type effervescent atomizer. Spray droplet size distributions were recorded by a Spraytec instrument. Increased shear viscosity in the range 24-836 mPa.s had a modest effect on spray mean diameters for pneumatic sprays of the Newtonian solutions of Hypromellose 5. In contrast, mean droplet diameters increased by a factor of 3-5 in pneumatic sprays of Povidone K-90F solutions 11-175 mPa.s in viscosity, where non-Newtonian behavior was observed. Further, sprays of all solutions of Povidone K-90F have considerably larger mean droplet size. The effervescent atomizer atomized low viscosity solutions of Povidone K-90F more efficiently than Hypromellose 5 solutions of corresponding shear viscosity. However, atomization of high viscosity Povidone K-90F results in a coarser spray than that of the corresponding Hypromellose 5 solution. Viscosity, visco-elasticity, and surface tension of solutions all seem to affect atomization efficiency. The pneumatic atomizer was not sensitive to changes in airflow above 8.4 kg/h and liquid flow only had a considerable effect at suboptimal air flows. In its current design the effervescent atomizer improved efficiency throughout the investigated range of air flow of 0.18-0.84 kg/h and consistently produced smaller drops at liquid flow of 10 g/min compared to 35 g/min. In spite of the very low level of air consumption, the effervescent atomizer can produce fine sprays. Within its working range, the standard pneumatic atomizer, however, is capable of producing sprays of even smaller mean droplet size. All together this suggests the described effervescent atomizer as an alternative for applications where advantages of reduced atomization air flow outweigh the disadvantages of a less fine spray, e.g., in coating of attrition-prone substrate.

Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug.

The influence of liquid intake and a lipid-rich meal on the bioavailability of a lipophilic drug was investigated. Danazol was used as the model substance. In a randomized four-way crossover study eight healthy male volunteers received four different treatments with danazol at 2-week intervals following an overnight fast (one I.V. infusion and three oral treatments). The I.V. formulation contained 50mg danazol solubilized in 40% hydroxypropyl-beta-cyclodextrin. The oral treatments were a Standard treatment, a Standard + 800 ml water treatment and a Standard + lipid-rich meal treatment. The Standard oral treatment consisted of 200 ml water and one capsule containing 100mg danazol, three 500 mg paracetamol tablets and two 500 mg sulfasalazine tablets. Paracetamol and sulfasalazine were used as markers for gastric emptying and small intestinal transit times. Intake of danazol with a lipid-rich meal or extra 800 ml water increased the bioavailability by 400 and 55%, respectively. Gastric emptying times increased in the following order: Standard

In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media.

The purpose of the study was to design dissolution tests that were able to distinguish between the behaviour of danazol under fasted and fed conditions, by using biorelevant media. In vitro dissolution of 100mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 ml, respectively. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Extract and soybean phospholipids, were used as the bile source. The effect of adding different concentrations and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Müllertz, A. 2005. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug, Eur. J. Pharm. Sci. 24, 297-303]. In the fasted state, the physiologically most relevant correlation with in vivo results was achieved with a medium containing 6.3 mM bile salts and 1.25 mM phospholipids (8 ml/min). A medium containing 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 ml/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissolution method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium composition were important for the dissolution of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.

Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols.

The partitioning of poorly soluble drugs into an aqueous micellar phase was exploited using an in vitro lipid digestion model, simulating the events taking place during digestion of acylglycerols in the duodenum. The aqueous micellar phase was isolated after ultracentrifugation of samples obtained at different degrees of triacylglycerol hydrolysis. Flupentixol, 1'-[4-[1-(4-fluorophenyl)-1-H-indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H), 4' piperidine] (LU 28-179) and probucol were studied. The effect of the alkyl chain length of the triacylglycerol was studied using a medium-chain triacylglycerol (MCT) and a long-chain triacylglycerol (LCT), respectively. In general, an oil solution was used as the lipid source in the model. Samples were analysed in regard to micellar size, lipid composition and drug concentration. During lipolysis, the content of lipolytic products in the aqueous micellar phase increased. The micellar size (R(H) approximately 3 nm) only increased when long-chain lipolytic products were incorporated in the mixed micelles (R(H) approximately 7.8 nm). Flupentixol was quickly transferred to the mixed micelles due to high solubility in this phase (100% released). A tendency towards higher solubilisation of LU 28-179, when it was administered in the LCT (approximately 24% released) compared to when it was administered in the MCT (approximately 15% released) at 70% hydrolysis, and a lagphase was observed. There was no difference in the solubilisation of probucol using MCT or LCT ( approximately 20% released), respectively. Differences in the physicochemical properties of the drugs resulted in differences in their distribution between the phases arising during lipolysis.

The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer.

The aim of this study was to prepare by melt agglomeration agglomerates containing solid dispersions of diazepam as poorly water-soluble model drug in order to evaluate the possibility of improving the dissolution rate. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 or Gelucire 50/13 (mixture of glycerides and PEG esters of fatty acids) as meltable binders in a high shear mixer. The binders were added either as a mixture of melted binder and diazepam by a pump-on procedure or by a melt-in procedure of solid binder particles. Different drug concentrations, maximum manufacturing temperatures, and cooling rates were investigated. It was found to be possible to increase the dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was obtained with a lower drug concentration. Admixing the binders by the melt-in procedure resulted in similar dissolution rates as the pump-on procedure. The different maximum manufacturing temperatures and cooling rates were found to have complex effects on the dissolution rate for formulations containing PEG 3000, whereas only minor effects of the cooling procedure were found with Gelucire 50/13. Gelucire 50/13 resulted in faster dissolution rates compared to PEG 3000.